Abstract: Clostridioides difficile infection (CDI) has a serious impact on the healthcare system, and most of its pathogenic effects are mainly due to the activity of toxins A and B (TcdA and TcdB, respectively). The molecular mechanisms of their cytotoxic activity are well known, especially in the colon, where the infection occurs and normally remains localized. However, the mechanisms causing toxic effects on various systemic organs (extraintestinal manifestations) with frequent lethal outcomes in some patients affected by CDI are still poorly understood. Few studies are available that demonstrate low serum levels of Tcds in both experimental animal models and patients with CDI. Until now, it has remained unclear how low levels of circulating Tcds could lead to serious toxic effects. On the basis of our previous in vitro studies, in which the proinflammatory cytokines TNF-alpha and IFN-gamma strongly potentiated the toxic activity of low doses of TcdB, we hypothesize that the presence of both TcdB in the circulation and a systemic proinflammatory cytokine storm may be responsible for the selective severe effects of TcdB in some patients. This may occur in patients with severe CDI and systemic Tcds, in whom proinflammatory cytokines such as TNF-alpha and IFN-gamma reach a significant concentration in the circulation. This hypothesis could identify therapeutic interventions based on the reduction or neutralization of the indirect toxic action of these cytokines.

Keywords: Clostridioides difficile, toxin B, proinflammatory cytokines, TNF-alpha, IFN-gamma, systemic effects


中文翻译：

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促炎性细胞因子：艰难梭菌毒素B的全身作用可能的帮凶

摘要： 艰难梭菌感染（CDI）对医疗保健系统有严重影响，其大部分致病作用主要归因于毒素A和B（分别为TcdA和TcdB）的活性。它们的细胞毒性活性的分子机制是众所周知的，尤其是在结肠中，在那里发生感染并且通常保持局部。然而，在一些受CDI影响的患者中，对具有频繁致死结果的各种全身器官（肠外表现）产生毒性作用的机制仍知之甚少。很少有研究表明在实验动物模型和CDI患者中Tcds的血清水平较低。到目前为止，仍不清楚循环中的Tcd含量低会如何导致严重的毒性作用。根据我们先前的体外研究，其中促炎细胞因子TNF-α和IFN-γ强烈增强了低剂量TcdB的毒性活性，我们假设循环中存在TcdB和系统性促炎性细胞因子风暴可能是TcdB选择性严重影响的原因在某些患者中。这可能发生在患有严重CDI和全身性Tcds的患者中，其中促炎性细胞因子（如TNF-α和IFN-γ）在循环系统中达到很高的浓度。该假设可以基于减少或中和这些细胞因子的间接毒性作用来确定治疗干预措施。我们假设循环中TcdB的存在和全身性促炎性细胞因子风暴可能是某些患者中TcdB选择性严重影响的原因。这可能发生在患有严重CDI和全身性Tcds的患者中，其中促炎性细胞因子（如TNF-α和IFN-γ）在循环系统中达到很高的浓度。该假设可以基于减少或中和这些细胞因子的间接毒性作用来确定治疗干预措施。我们假设循环中TcdB的存在和全身性促炎性细胞因子风暴可能是某些患者中TcdB选择性严重影响的原因。这可能发生在患有严重CDI和全身性Tcds的患者中，其中促炎性细胞因子（如TNF-α和IFN-γ）在循环系统中达到很高的浓度。该假设可以基于减少或中和这些细胞因子的间接毒性作用来确定治疗干预措施。

关键词： 艰难梭菌，毒素B，促炎细胞因子，TNF-α，IFN-γ，全身作用